Indian Long-term Non-Progressors Show Broad ADCC Responses with Preferential Recognition of V3 Region of Envelope and a Region from Tat Protein

Abstract

HIV-specific antibody-dependent cell cytotoxicity (ADCC) is likely to be important in governing protection from human immunodeficiency virus (HIV) and slowing disease progression. Little is known about the ADCC responses to HIV-1 subtype C. We characterized ADCC responses in HIV-1 subtype C-infected Indian subjects with slow disease progression and identified the dominant antigenic regions recognized by these antibodies. ADCC responses were measured in plasma from 34 long-term non-progressors (LTNPs), who were asymptomatic and maintained CD4 count above 500 cells/mm3 for the last 7 years in the absence of antiretroviral therapy (ART), and 58 ART naïve progressors with CD4 count <500 cells/mm3 against overlapping HIV-1 peptides using a flow cytometry-based antibody-dependent natural killer (NK) cell activation assay. The assay measured CD107a expression on NK cells as a marker of antibody-dependent NK cell activation and IFN-γ secretion by NK cells upon activation. The ADCC epitopes were mapped using the matrix of overlapping peptides. Indian LTNPs showed higher and broader ADCC responses compared to the progressors. The Env-C and Tat-specific ADCC responses were associated with lower plasma viral load, whereas the Env-C responses were also associated with higher CD4 counts. Five of 10 LTNP responders targeted epitopes in the V3 region (amino acids 288–330) of Env-C. Additionally, three Tat regions were targeted by ADCC antibodies from LTNPs. ADCC responses were associated with slow HIV progression in Indian subtype C-infected cohort. The frequently recognized peptides from the V3 loop of Env and the novel epitopes from Tat by the LTNPs warrants further study to understand the role of ADCC responses to these regions in control and prevention of HIV-1 infection.

Common antibody dependent cell mediated cytotoxicity (ADCC) antibody epitopes of HIV-1 CRF01_AE Env and Gag in early HIV-1 infected individuals

“…Thus, the ADCC antibody at the non-early phase would not be able to respond to these original V3 epitopes as we previously reported on ADCC epitopes of HIV-1 in asymptomatic infected individuals. 12 Our finding of peptide 85 (aa 336-350: GTKWNEVLKKVTKKL) as dominant ADCC epitope was also correspondent to the data of Kulkarni et al 15 They demonstrated the recognition of novel antigenic ADCC epitope in sera of LTNPs at the C3 region (aa 331-360: CNISEEKWNKTLQRVSEKLKEHFPNKTIKF).…”

“…15 They proposed the potential role of this anti-V3 ADCC response in viral control which may contribute to the slower disease progressors. Their epitope sequences included our full epitope peptide 78 (aa 308-322: SINIGPGQVFYRTGD) and partial of epitope peptide 71 (aa 290-294:…LNKSV).…”

The Antibodiome—Mapping the Humoral Immune Response to HIV

“…Specifically, ECs and LTNPs appear to have enhanced ADCC response and target both the viral Env and regulatory/accessory viral proteins, such as Vpu, that are not observed in progressors [ 66 •]. Moreover, ADCC activity against the structural Env V3 loop region as well as against Gag and Tat proteins is disproportionately higher in controllers [ 78 , 79 ]. Importantly, although abundant, ADCC is not the only innate effector function induced at high levels in controllers.…”

Natural Killer (NK) Cell Education Differentially Influences HIV Antibody-Dependent NK Cell Activation and Antibody-Dependent Cellular Cytotoxicity

“…As opposed to ADNKA, ADCC measures target cell phenomena arising from the bridging of effector and target cells by an Ab whose Fc portion binds CD16 on effector cells and whose Fab portion recognizes an antigen on target cells. In the context of ADCC function-directed HIV Env gp120-coated target cells, the target antigens recognized by ADCC competent Abs are HIV Env ( 30 , 78 , 100 ). ADCC activity directed to HIV infected may also recognize Tat ( 100 ).…”

“…In the context of ADCC function-directed HIV Env gp120-coated target cells, the target antigens recognized by ADCC competent Abs are HIV Env ( 30 , 78 , 100 ). ADCC activity directed to HIV infected may also recognize Tat ( 100 ).…”